Burimamide (IIa) was the first clinically effective H.sub.2 -receptor antagonist. It inhibits gastric secretion in animals and man, but oral absorption is poor. ##STR2## IIa; R.sup.2 .dbd.H, Z.dbd.CH.sub.2, X.dbd.S Burimamide b; R.sup.2 .dbd.CH.sub.3, Z.dbd.S, X.dbd.S Metiamide
c; R.sup.2 .dbd.CH.sub.3, Z.dbd.S, X=NCN Cimetidine
Metiamide (IIb), a subsequently evaluated H.sub.2 -antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc) is as effective an H.sub.2 -antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug.
Reviews on the development of H.sub.2 -antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future 1, 13 (1976), and in references cited therein. Relevant patents are as follows:
U.S. Pat. No. 4,098,898 is representative of a large number of patents disclosing broad classes of histamine H.sub.2 -antagonists which are N,N'-(disubstituted)thioureas, N,N'-(disubstituted)guanidines and/or N,N'-disubstituted-1,1-diaminoethylenes in which at least one of the N-substitutents is a broadly defined heterocyclylalkylthioalkyl, heterocyclylalkoxyalkyl or heterocyclylalkyl moiety. The heterocyclyl ring is often broadly defined as being a 5- or 6-membered N-containing heterocyclic ring which optionally contains additional hetero atoms selected from N, S and O, and which is optionally substituted. U.S. Pat. No. 4,098,898 discloses compounds of the formula ##STR3## wherein X is sulfur, CHNO.sub.2, NCN or NH; Y is amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl, 2,2,2-trifluoroethyl or (CH.sub.2).sub.n R; Z is sulfur or methylene; Het is an imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, triazole or thiadiazole ring which is optionally substituted by (lower)alkyl, hydroxy, halogen or amino; n is 1-12; and R is hydroxy, (lower)alkoxy, amino or (lower)alkylamino; provided that when X is NH, Y is 2,2,2-trifluoroethyl or (CH.sub.2).sub.n R and that when X is NCN, Y is not amino or (lower)alkylamino.
U.S. Pat. No. 4,062,863 discloses histamine H.sub.2 -antagonists of the formula ##STR4## wherein R is hydrogen, (lower)alkyl or --(CH.sub.2).sub.2 Z'CH.sub.2 Het'; Z and Z' each are sulfur or methylene; and Het and Het' each are an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or an isothiazole ring; and pharmaceutically acceptable acid addition salts thereof. U.S. Pat. Nos. 4,120,968 and 4,120,973 are related cases having substantially identical disclosures.
U.S. Pat. No. 4,104,381 discloses histamine H.sub.2 -antagonists of the formula ##STR5## wherein Het is a nitrogen-containing heterocycle such as imidazole, pyridine, thiazole, isothiazole or thiadiazole which is optionally substituted by (lower)alkyl, amino, hydroxy or halogen; Z is sulfur or methylene; n is 2 or 3; and A, taken together with the nitrogen and carbon atoms to which it is attached, forms a pyrimidine, imidazoline, quinazoline, pyridine, benzothiadiazine, 1,2,4-thiadiazine, thiazoline, 1,2,4-triazine or quinoline ring, said ring having a keto, thione or sulfone group and being optionally substituted by one or two (lower)alkyl, phenyl or benzyl groups; and pharmaceutically acceptable acid addition salts thereof. This patent includes within its scope, and states to be one of four "particularly important" classes, substituted 1,2,4-thiadiazine compounds of the formula ##STR6## wherein Het is as defined above, Z is sulfur or methylene, and Y.sup.1 and Y.sup.2 are independently hydrogen, (lower)alkyl, phenyl or benzyl, or Y.sup.1 and Y.sup.2, taken together with the adjacent carbon atoms, may form a fused phenyl ring. U.S. Pat. Nos. 3,932,644, 4,005,205, 4,035,374 and 4,153,793 are related cases having substantially the same disclosure.
Belgian Pat. No. 864,992 discloses compounds which are simultaneously histamine H.sub.1 -antagonists and histamine H.sub.2 -antagonists having the formula ##STR7## wherein Het' is a 2- or 4-benzimidazolyl ring which is optionally substituted by (lower)alkyl, halogen, CF.sub.3 or CH.sub.2 OH, a 2-pyridyl ring which is optionally substituted by 1 or 2 (lower)alkyl, (lower)alkoxy, halogen, amino or OH groups, a 2-pyridyl ring condensed with a phenyl group or with a cyclic ether containing 2 oxygen atoms, a 2-thiazolyl ring, a 3-isothiazolyl ring which is optionally substituted by Cl or Br, a 1,2,5-thiadiazol-3-yl ring which is optionally substituted by Cl or Br, or a 5-amino-1,3,4-thiadiazol-2-yl ring; Z' is CH.sub.2 or S; x is 1-5; Y is 1- or 2-naphthyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, phenyl substituted by one or more alkyl, (lower)alkoxy, halogen, aralkoxy, OH, alkoxyalkoxy, CF.sub.3, di(lower)alkylamino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl groups, or Y is a 5- or 6-membered heterocyclyl ring which is optionally substituted by a (lower)alkyl or (lower)alkoxy group, and optionally has a fused benzene ring; and when x is 2-5, Y may also be phenyl.
U.S. Pat. No. 4,128,658 discloses histamine H.sub.2 -antagonists of the formula ##STR8## wherein R.sub.1 and R.sub.2 are hydrogen, (lower)alkyl, cycloalkyl, (lower)alkenyl, aralkyl or (lower)alkyl interrupted by an oxygen atom or the group --N(R.sub.4)-- in which R.sub.4 is hydrogen or (lower)alkyl, or R.sub.1 and R.sub.2 taken together with the N atom to which they are attached may form a heterocyclic ring optionally containing other heteroatoms selected from O and --N(R.sub.4)--; R.sub.3 is hydrogen, (lower)alkyl, (lower)alkenyl or alkoxyalkyl; X is --CH.sub.2 --, O or S; Y is S, O, NR.sub.5 or CHR.sub.6 ; Alk is a straight or branched alkylene chain of 1 to 6 carbon atoms; R.sub.5 is H, NO.sub.2, CN, (lower) alkyl, aryl, alkylsulfonyl or arylsulfonyl; R.sub.6 is NO.sub.2, arylsulfonyl or alkylsulfonyl; m is an integer of from 2 to 4; n is 1 or 2, or, when X is S or CH.sub.2, n is 0, 1 or 2; and physiologically acceptable salts, hydrates and N-oxides thereof. The disclosure of U.K. Published Application No. 2,006,771 is substantially the same as U.S. Pat. No. 4,128,658 except that X may not be methylene, and the furan ring has a substitutent adjacent the dialkylaminoalkyl group which is selected from (lower)alkyl, (lower)alkoxy(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxycarbonyl, (lower)alkylthio(lower)alkyl, halogen and aryl.
The disclosure of Belgian Pat. No. 867,106 is similar to that of U.S. Pat. No. 4,128,658, except that the disubstituted furyl ring is replaced by a similarly disubstituted phenyl ring.
The disclosure of Belgian Pat. No. 867,105 is similar to that of U.S. Pat. No. 4,128,658 except that the disubstituted furyl ring is replaced by a similarly disubstituted thienyl ring.
U.K. Published Patent Application No. 2,001,624 discloses histamine H.sub.2 -antagonists of the formula ##STR9## wherein X is S or NH; Y is O, S, SO, CH.sub.2, a direct bond or a vinylene radical; m is 0 to 4; n is 1 to 4; R.sup.1 is H, halogen or alkyl; R.sup.2 is hydrogen, alkyl, alkanoyl or aroyl; A is a 3,4-dioxocyclobuten-1,2-diyl radical or C.dbd.Z in which Z is O, S, NCN, NNO.sub.2, CHNO.sub.2, NCONH.sub.2, C(CN).sub.2, NCOR.sup.3, NCO.sub.2 R.sup.3, NSO.sub.2 R.sup.3 or NR.sub.4 in which R.sup.3 is alkyl or aryl and R.sup.4 is hydrogen or alkyl; B is alkoxy, alkylthio or NR.sup.5 R.sup.6 in which R.sup.5 and R.sup.6 are independently hydrogen, alkyl, alkenyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl or dialkylaminoalkyl; and salts thereof.
Belgian Pat. No. 886,155 discloses histamine H.sub.2 -antagonists of the formula ##STR10## wherein R.sup.1 is H or (lower)alkyl; Y is S or CH.sub.2 ; and Z is S or NCN; and pharmaceutically acceptable acid addition salts thereof.
U.S. Pat. No. 4,112,234 discloses histamine H.sub.2 -antagonists of the formula ##STR11## wherein R.sup.1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms; and nontoxic pharmaceutically acceptable salts thereof.
U.S. Pat. No. 4,145,546 discloses compounds which are simultaneously histamine H.sub.1 -antagonists and histamine H.sub.2 -antagonists, having the formula ##STR12## wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by (lower)alkyl, halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by (lower)alkyl, (lower)alkoxy, halogen, amino or hydroxy, a 2-pyridyl ring which is disubstituted by (lower)alkoxy groups or which has a phenyl, carbocyclic or cyclic ether ring containing two oxygen atoms fused to it, a 2-thiazolyl ring, a 3-thiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5-thiadiazolyl) ring optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl) ring; Z is sulfur or methylene; X is oxygen or sulfur; W is methylene, oxygen or sulfur; m and n are such that their sum is from 1 to 4 when W is oxygen or sulfur, or from 0 to 4 when W is methylene; A is a 1-or 2-naphthyl ring, a 2,3-dihydro-1,4-benzodioxinyl ring, a 1,3-benzodioxolyl ring or a phenyl ring substituted by one or more (lower)alkyl, (lower)alkoxy, halogen, arylalkoxy, hydroxy, (lower)alkoxy(lower)alkoxy, trifluoromethyl, di(lower)alkylamino, phenoxy, halophenoxy, (lower)alkoxyphenoxy, phenyl, halophenyl or (lower)alkoxyphenyl groups; and when --(CH.sub.2).sub.m W(CH.sub.2).sub.n -- is not a methylene group, A may also be phenyl; and Y.sup.3 is hydrogen or (lower)alkyl; and acid addition salts thereof. The disclosure of U.S. Pat. No. 4,159,329 is substantially the same as that of U.S. Pat. No. 4,145,546. The disclosure of U.S Pat. No. 4,154,834 is substantially the same as that of U.S. Pat. No. 4,145,546, except that A is a 5- or 6-membered heterocyclic ring selected from pyridine, pyridine-N-oxide, furan, thiophene, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine, pyridazine and thiadiazole, which are optionally substituted by 1 or 2 (lower)alkyl, (lower)alkoxy, halogen, hydroxy or amino groups, or A is a pyridine ring with a carbocyclic or cyclic ether ring containing two oxygen atoms fused to it; or A is a pyridine, imidazole or thiazole ring having a benzene ring fused to it.
U.K. Published Patent Application No. 2,023,133 discloses histamine H.sub.2 -antagonists of the formula ##STR13## wherein R.sub.1 and R.sub.2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, or R.sub.1 and R.sub.2, taken together with the nitrogen to which they are attached, may be a 5 to 10-membered alicyclic heterocyclic ring which may be saturated or may contain at least one double bond, which may be substituted by one or more alkyl groups or a hydroxy group and/or which may contain another heteroatom; Alk is a straight or branched alkylene chain of 1-6 carbon atoms; Q is a furan or thiophene ring incorporated into the molecule via the 2- and 5-positions, the furan ring optionally bearing a further substituent R.sub.7 adjacent the R.sub.1 R.sub.2 N-Alk-group, or Q is a benzene ring incorporated into the molecule via its 1- and 3- or 1- and 4-positions; R.sub.7 is halogen, alkyl (which may be substituted by hydroxy or alkoxy); X is methylene, oxygen, sulfur or &gt;N--R.sup.6 in which R.sup.6 is hydrogen or methyl; n is 0, 1 or 2; m is 2, 3 or 4; R.sub.3 is hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl having at least two carbon atoms, alkoxyalkyl or aryl; and R.sub.4 and R.sub.5 are independently hydrogen, alkyl, alkyl substituted by hydroxy or C.sub.1-3 alkoxy, alkenyl, aralkyl or heteroaralkyl, or R.sub.4 and R.sub.5 taken together with the nitrogen to which they are attached, may be a 5 to 7-membered saturated heretocyclic ring which may contain another heteroatom or the group &gt;NR.sup.6, or R.sub.4 and R.sub.5 taken together may be the group &gt;CR.sub.8 R.sub.9 wherein R.sub.8 is aryl or heteroaryl and R.sub.9 is hydrogen or alkyl; and physiologically acceptable salts and hydrates thereof.
Although the three other isomeric thiadiazoles (the 1,2,3-, 1,2,4- and 1,3,4- isomers) were known previously, 1,2,5-thiadiazole was first prepared in 1958. Since that time a large number of 3-substituted- and 3,4-disubstituted-1,2,5-thiadiazoles have been reported in the literature, including a small number of simple 3,4-di(substituted amino)-1,2,5-thiadiazoles, e.g. the 3,4-bis(dimethylamino) compound. See , for example the review in Advances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Eds., 9, 107-163, Academic Press, New York (1968) and the publications in J. Het. Chem., 13, 13 (1976) and J. Med. Chem., 15, 315 (1972). A moderate number of 3,4-disubstituted-1,2,5-thiadiazole 1,1-dioxides are known, including the 3,4-dichloro-, 3,4-dimethoxy- and 3,4-diethoxy useful as starting materials for the preparation of compounds of Formula I in which p is 2. 3,4-Diamino- and a small number of simple 3,4-di(substituted amino)-1,2,5-thiadiazole 1,1-dioxides are known, e.g. the bis(methylamino)-, bis(dimethylamino)- and bis(o-carboxyphenylamino)- compounds. See, for example, the abovecited review article and J. Org. Chem., 40, 2743 (1975). Similar derivatives of 1,2,5-thiadiazole 1-oxide have not been reported. Certain 3-hydroxy-4-(substituted amino) derivatives of 1,2,5-thiadiazoles are known. For example, J. Org. Chem., 41, 3121 (1976) reports the synthesis of 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole and J. Org. Chem., 40, 2743 (1975) reports the preparation of 3-hydroxy-4-(N-piperidino)-1,2,5-thiadiazole 1,1-dioxide. Correspondingly substituted 1,2,5-thiadiazole 1-oxides apparently are not known. To our knowledge, the only reported disubstituted 1,2,5-thiadiazole 1-oxide is the 3,4-dihydroxy compound. None of the 3,4-disubstituted-1,2,5-thiadiazole derivatives of the present invention are known. None of the above-cited known 3,4-disubstituted-1,2,5-thiadiazole derivatives have been reported to have H.sub.2 -antagonist or anti-ulcer activity.